Combination AIDS vaccines, using live recombinant vectors as priming vehicles followed by protein booster inoculations, are promising. Adenovirus (Ad)-HIV-1(MN) envelope recombinants followed by gp120 (SF2 strain) have protected chimpanzees from both low- and high-dose infection with HIV-1(SF2). Significant advances include the following points: 1) Long-lasting protection can be achieved with only 1 priming immunization and 2 protein boosters, or 2 primings and 1 booster; 2) the high-titered neutralizing antibodies elicited were persistent; 3) one protected chimpanzee lacking neutralizing antibodies but possessing HIV envelope-specific cytotoxic T-lymphocytes (CTL) was protected from low-dose challenge, suggesting for the first time a role for CTLs in vaccine protection; 4) the vaccine regimen elicited antibodies capable of neutralizing primary isolates, not previously demonstrated with other approaches; 5) protection against a high-dose challenge with no intervening booster inoculation persisted for >50 weeks. The protection that was achieved resulted from only Ad-envelope priming and gp120 boosting. Enhanced protection would be expected from a similar approach incorporating HIV gag and nef genes and gene products. Further vaccine studies in macaques have used an Ad 5 host range mutant vector carrying the SIV envelope gene, combined with a native SIV envelope subunit. This approach elicited humoral, cellular, and mucosal immune responses in immunized macaques. The mucosal immunity is particularly encouraging, as approximately 95% of all HIV transmissions worldwide occur across mucosal barriers. The ability of this vaccine approach to protect against intravaginal and intrarectal transmission is being evaluated. Similar prime-boost approaches are being carried out using attenuated poxvirus vectors as vaccine vehicles. Earlier studies showed that immunization with HIV-1 recombinants and proteins resulted in protection against HIV-2 challenge, suggesting that development of a single globally effective AIDS vaccine might be possible. We are expanding this study to confirm the previous result and identify the nature of the cross-protective immunity. Finally, results of studies on immune escape variants have highlighted the CD4 binding site region as crucial for envelope function and immune recognition. We have shown that a conformationally constrained helical peptide from the CD4 binding site region appropriately models the native site and provides an explanation for how such disparate viruses, as HIV-1, HIV-2, and SIV, can all recognize the CD4 receptor. Vaccine approaches using this helical peptide are in progress.